Immune system modulators
Gabriel Virella in Medical Immunology, 2019
TNF has been implicated as one of the primary cytokines responsible for inflammation in several diseases, including rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. Several different medications have been developed to inhibit TNF in a number of ways. Etanercept exists as an artificial, plasma-based version of the TNF receptor that binds to TNF before it is able to interact with cell-bound receptors and initiate the inflammatory cascade. It is typically administered as a weekly subcutaneous injection. Infliximab is a monoclonal anti-TNF antibody that is a murine/human hybrid. It functions by binding and neutralizing TNF in the plasma and is given as an IV infusion every 6–8 weeks. Due to its chimeric nature, however, use of this medication can lead to development of antichimeric antibodies that can lower the functional level of the drug, making it less effective. Adalimumab differs in that it is a fully humanized monoclonal antibody to TNF. This theoretically lowers the immunogenicity of the molecule. Adalimumab is given as a subcutaneous injection every 7–14 days. Similar to adalimumab, golimumab also is a monoclonal antibody, and its longer half-life allows the medication to be given on a monthly basis subcutaneously or every 2 months intravenously. Finally, certolizumab is another TNF inhibitor, in this case a pegylated F(ab′)2 fragment of anti-TNF antibody. Its half-life is shorter (11 days) and thus it needs to be administered initially every 2 weeks and every 4 weeks for maintenance of its effects.
Pediatric psoriasis
M. Alan Menter, Caitriona Ryan in Psoriasis, 2017
Serious adverse events are rare in children. Patients may be at risk for mycobacterial and salmonella infections97and baseline and annual tuberculosis (TB) testing (by PPD, quantiferon-gold, or Interferon-gamma release assay) is recommended. The long-term side effects in children are unknown and adverse effects on immune system development and an increased risk of lymphoma are theoretical concerns. Although TNF inhibitors carry a black box warning for an increased risk of malignancy, no cases of lymphoma have been reported in pediatric psoriasis. TNF inhibitors can show loss of efficacy with time; in adults, the 4-year drug survival for etanercept or adalimumab is approximately 40%.98 Should a TNF inhibitor lose its efficacy, an alternative TNF inhibitor (or different class of medication) can significantly improve psoriasis severity.
Allogeneic Hematopoietic Stem Cell Transplantation for Autoimmune Diseases
Richard K. Burt, Alberto M. Marmont in Stem Cell Therapy for Autoimmune Disease, 2019
In case reports of allogeneic HSCT in patients with coincidental rheumatoid arthritis (RA), almost all patients had sustained remissions without evidence of RA after HSCT. A subset of RA patients with more than 20 involved joints or significant limitations on their health assessment questionnaire have a 5 year mortality of 40%. For these patients, HSCT from an HLA matched sibling could be considered. High risk patients eligible for this therapy may be defined as: An established clinical diagnosis of rheumatoid arthritis by American College of Rheumatology criteria and failure to respond to at least 3 months of either methotrexate or leflunomide in combination with a TNF inhibitor. Failure being defined as at least 12 swollen joints and 20 involved joints or inability to answer at least 70% of HAQ questions with “no difficulty”.
Approval of biosimilars: a review of unsuccessful regulatory filings
Published in Expert Opinion on Biological Therapy, 2021
Anurag S. Rathore, Hemlata Chhabra, Ankita Bhargava
EMA was the first regulatory agency to start reviewing applications for biosimilars approval. To date, EMA has approved 64 biosimilars within the product classes of 1) human growth hormone, 2) granulocyte colony-stimulating factor, 3) erythropoiesis-stimulating agent, 4) insulin, 5) follicle-stimulating hormone (FSH), 6) parathyroid hormone, 7) tumor necrosis factor (TNF) inhibitor, and 8) monoclonal antibodies for use in the EU [11]. Thus, far nine biosimilar approvals have been withdrawn after approval, one biosimilar has been withdrawn before approval, and two biosimilar applications have been refused by the agency (Table 1). This leaves a total of 55 biosimilars authorized for use in Europe [12]. In spite of the patent expiration in EU for Erbitux (cetuximab) and Aranesp (darbepoetin alfa) in 2014 and 2016, respectively, no biosimilars have been approved for the same. A number of biosimilar products for cetuximab including ABP-494 (Actavis/Amgen) and CT-P15 (Celltrion) are in development [13]. Two products, Retacrit (Hospira) and Silapo (Stada), are being approved by EMA for similar indications such as Aranesp including anemia, chronic kidney failure, cancer, and autologous blood transfusion. The reference medicine for both the products is Eprex/Erypo, which contains epoetin alpha as an active substance. [14]. Other blockbuster drugs that are set to lose their patents in the coming 2 years in Europe include Soliris (2020), Benlysta (2021), Lemtrada (2021), Avastin (2022), and Lucentis (2022) [15].
Drug survival rates of biological disease-modifying antirheumatic drugs and Janus kinase-inhibitor therapy in 801 rheumatoid arthritis patients: a 14 year-retrospective study from a rheumatology clinic in Japan
Published in Modern Rheumatology, 2019
Masakazu Kondo, Hisakata Yamada
The biological formulations administered in this study and the respective dates of introduction and numbers of subjects who received the drugs were as follows: (i) IFX, 2003, 87 subjects; (ii) ETN, 2005, 247 subjects; (iii) TCZ (subcutaneous injection, 47.3%), 2008, 167 subjects; (iv) ADA, 2008, 114 subjects; (v) ABT (subcutaneous injection, 13.6%), 2010, 66 subjects; (vi) GLM, 2011, 81 subjects; and (vii) CZP, 2013, 21 subjects. The JAK inhibitor, tofacitinib (TOF), was introduced in 2013 and administered to 18 subjects (Figure 1). Many of the subjects in the naïve group were administered a tumor necrosis factor (TNF)-inhibitor. The drugs used in the switch cases were, as a general rule, a TNF inhibitor up to the second drug and an interleukin (IL)-6 inhibitor as the third drug. If these biological drugs were found to have no effect, a JAK-inhibitor was selected.
The advent of IL-17A blockade in ankylosing spondylitis: secukinumab, ixekizumab and beyond
Published in Expert Review of Clinical Immunology, 2019
Sayam Dubash, Charlie Bridgewood, Dennis McGonagle, Helena Marzo-Ortega
Historically, AS therapies have been limited to mainly physiotherapy and non-steroidal anti-inflammatory drugs (NSAIDs). In the last two decades, major therapeutic progress has been made with the advent of the TNF inhibitor (TNFi) biologic drugs, which have produced a huge impact on patient outcomes and substantially ameliorated AS in many patients. Despite the availability of several TNFi therapies for AS, there is still a need for alternative modes of action particularly as up to 40% of AS patients do not demonstrate a meaningful clinical response to TNFi [3,4]. Further, TNFi may be contraindicated for certain patients and given the lack of efficacy of conventional disease modifying anti-rheumatic drugs (cDMARDs) for axial symptoms in AS, the need for an additional class of biologic was overdue [3,5–7].
Related Knowledge Centers
- Ankylosing Spondylitis
- Asthma
- Inflammation
- Inflammatory Bowel Disease
- Tumor Necrosis Factor
- Tuberculosis
- Psoriasis
- Hidradenitis Suppurativa
- Medication
- Rheumatoid Arthritis